Post-traumatic stress disorder (PTSD) occurs only in vulnerable individuals after exposure to severe traumatic events. This differential risk is due in part to vulnerability and resilience that is 30- 40% heritable. Thus, PTSD is among the most likely of psychiatric disorders to be understood from the perspective of environmental influences interacting with genetic vulnerability, since diagnosis requires a specific, highly traumatizing experience. In the first 4.5 years of this NIMH-supported project, our group has collected a large, valuable sample set and demonstrated significant gene- environment interactions in PTSD through our hypothesis-driven efforts in a highly traumatized population. In the competitive renewal, we propose to use state-of-the-art genetic approaches to identify, in a hypothesis-neutral fashion, which genes are the most likely to contribute to PTSD. The proposed genome-wide association study (GWAS) involving N=8,000 subjects will leverage and expand our current set of PTSD samples. Focusing on subjects from a population with similar environmental exposure to a high trauma burden (4000 affected, 4000 unaffected) will allow us to identify a set of genetic variants associated with the presence or absence of PTSD symptoms in subjects with a common environmental background. This design is ideal for identifying variants which interact with environmental factors such as trauma but does not suffer from the lower power which characterizes typical GxE studies. To validate variants associated with PTSD in the proposed GWAS, we will employ additional well-characterized replication samples of traumatized subjects, including 1) a Caucasian sample with N=3,500 traumatized subjects, and 2) a sample of N=2,500 primarily African Americans from St. Louis. We are also joining efforts with several other PTSD researchers nationwide for future consortia and meta-analytic approaches, to eventually be combined with the N=14,000 examined within this application. We hypothesize that by focusing on genes and markers that are associated with the presence vs. absence of PTSD within a highly-traumatized population, we will have the greatest likelihood for prioritizing and replicating genetic variants involved in the etiology of PTSD. Our increasing understanding of the neural circuitry of fear dysregulation, combined with identification of genetic pathways that contribute to PTSD, will lead to an improved neurobiological understanding, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome. PUBLIC HEALTH RELEVANCE: Up to 40% of the variance determining who develops Posttraumatic Stress Disorder following a severe trauma is genetically heritable. By focusing on genes that differentially associate with presence or absence of PTSD in a similarly highly- traumatized population, we will successfully prioritize genes with a high likelihood of critical involvement in the etiology of PTSD. Identifying the genetic pathways involved with PTSD, combined with our increasing understanding of the neural circuitry of fear and stress-dysregulation, will lead to an improved neurobiological understanding, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome.